A. Field of invention
The present invention relates generally to methods of therapeutically treating cancer and more particularly to a new and improved method of administering ascorbic acid as a therapeutic agent.
B. Description of Related Art
In the treatment of cancer, surgical intervention may, in some cases, be effective, but it is generally understood that an effective method of treating malignancies on a cellular basis is desirable. A frequently used treatment mode for malignant tumors is the administration of a chemical agent that is selectively toxic to the neoplastic cells within the tumor, without being prohibitively toxic to the patient in general. A number of such agents have been used and are being used with varying degrees of success, but in general the successful use of such known chemotherapeutic agents is restricted by the toxicity of the agent and the corresponding side effects to the patient. Due to the limited effectiveness of such known agents, none of the known treatments qualifies as a satisfactory treatment for the condition. While a number of schemes for reducing the side effects of administering such chemotherapeutic agents have and are being studied and being attempted, including selective site delivery systems, such schemes have not succeeded to the point of eliminating the need for an agent that is more selectively toxic.
Known adverse side effects of administration of known chemotherapeutic agents include hair loss, nausea and vomiting, cardiac toxicity and secondary cancers, as well as bone marrow suppression leading to immune suppression and hematopoietic dysfunctions. A side effect of immunological suppression is particularly undesirable because of infectious complications in an immune suppressed patient can be severe and even fatal.
It is known that ascorbic acid and salts thereof have shown a cytotoxic effect when administered in vitro to tumor cell lines. For the purposes of this application, a reference to ascorbic acid includes the anionic component, ascorbate whether as an acid or one of the pharmaceutically acceptable salt thereof, most notably including sodium ascorbate and calcium ascorbate, any of which are included in a reference to "ascorbic acid" or "ascorbate". The cytotoxic effect of ascorbic acid is understood to relate to the increased production of intracellular hydrogen peroxide, which is more toxic to tumor cells due to the lower levels of catalase typically present in tumor cells as compared to normal cells. Although some cancers may respond to lower levels, the concentration level of ascorbic acid required for in vitro cytotoxic effectiveness are normally in the range of 5-40 mg/dl with concentrations of 30-40 mg/dl being typical. Since normal plasma levels of ascorbic acid range from 0.39-1.13 mg/dl and the highest levels generally achievable in humans by oral supplementation is 4.5 mg/dl, it has not been known how cytotoxically effective levels of ascorbic acid could be achieved in vivo, and whether the dosage required to attain such levels could be safely administered. Moreover, since ascorbic acid is readily cleared from the body, the tumor cytotoxic effect, if any, achieved by conventionally administered doses of ascorbic acid would be transitory at best.
At least two studies have found a failure of high doses of ascorbic acid to have the desired effect in the treatment of cancer, namely: Creagan, E. T.; Moertel, C. G.; O'Fallon, J. R.; et al. Failure of High Dose Vitamin C (ascorbic acid) to Benefit Patients With Advanced Cancer: A Control Trial. N Engl. J. Med., 1979; 301:687-690 and Mortel, C. G.; Fleming, T. R.; Creagan, E. T.; , et al. High Dose of Vitamin C Versus Placebo In The Treatment of Patients With Advanced Cancer Who Have Had No Prior Chemotherapy. N Engl. J. Med., 1985; 312:137-141. Heretofore the highest dosage understood to be safely administered to a human was approximately 10-15 grams. It is believed that the reported results demonstrate that oral administration of doses in the 10-15 gram range, considered maximum safe dosage, does not achieve cytotoxic levels of ascorbic acid in the patient's blood and that those reported beneficial effects of such dosages are the result of the increase in collagen which serves to isolate the neoplasm in cancer patients, due to the function of ascorbic acid as a cofactor in the enzymatic hydroxylation of proline residues of collagen to form hydroxyproline residues. The generally slight, marginal or negative results demonstrate that there was little or no direct cytotoxic effect of the ascorbic acid administered to the tumor cells in prior in vivo studies. The positive results are believed to have been achieved by means of increased stromal resistance to the invasiveness of the malignancies studied, although the lack of monitoring of the level of ascorbic acid present in the plasma prevents an accurate assessment.
There have been reports of rare instances of wide-spread tumor necrosis and hemorrhage in rare cases of extreme tumor sensitivity to ascorbic acid. Such results are not only rare but, being fatal, do not argue for the use of ascorbic acid as a therapeutic agent. In addition, it is known that the cytotoxic effect of ascorbic acid is diminished, to varying degrees, by the exposure to plasma. Therefore, the in vitro results are not readily duplicated in vivo and the concentrations of ascorbic acid that are effectively toxic in vitro are not as effective, nor as easy to achieve, in test subjects.
The prior studies related to ascorbic acid in cancer therapy, have not demonstrated that tumor-toxic ascorbic acid plasma levels could be achieved. Most of the prior art used oral ascorbate as an adjunct to other therapeutic options. Although some describe the use of intravenous ascorbate, the purpose was simply to deliver the dosage rather manipulate the plasma concentration over time, and therefore no effort has been made to measure plasma levels and no treatment has been described based upon maintenance of those levels at a concentration high enough to be cytotoxic to tumor cells continued over a significant period of time.